Recent in vitro evidence by this group and others predicts that apoptosis may be one of the pathways leading to cell death in AD. The cell death program is initiated in response to several stimuli, such as beta-amyloid (Ab), related analogs, or conditions causing excessive oxidative injury to the cells. This proposal centers on employing Ab, select derivatives, and a newly developed hydrogen peroxide model to initiate the cell death program and study the mechanisms of cell death in response to those stimuli at the molecular level. An interactive in vitro/in vivo approach employing well defined cell culture techniques and well characterized postmortem tissues will be used. In this way, they can evaluate the factors and molecular pathways that lead to neuronal dysfunction and death in AD. The secondary hypothesis is that specific cascades of immediate early genes (IEGs) participate in the neuronal cell death program. They will examine the response and profile of immediate early genes (IEGs) elicited by Ab and related analogs. It is predicted that select analogs initiating apoptosis will induce select IEGs and that these IEGs will both mediate and serve as molecular signatures of apoptosis. They will compare the IEG response initiated by Ab to that elicited by excessive oxidative injury caused by hydrogen peroxide.